The invention relates to the use of polycyclic 2-aminothiazole systems and of their physiologically tolerated salts and physiologically functional derivatives for producing medicines for the prophylaxis or treatment of obesity.
2-Aminothiazole systems are described as anti-inflammatory substances in R. Gupta et al., Indian J. Pharm. Sci. 1991, 53, 245-248.
The invention was based on the object of providing compounds which display a therapeutically utilizable anorectic effect.
The invention relates to a method for the treatment of obesity comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I: 
in which
Y is a direct linkage, CH2 or CH2xe2x80x94CH2;
X is CH2, O, NH, NR6 or S;
R1, R1xe2x80x2 are independently H, F, Cl, Br, I, CF3, CN, NO2, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, Oxe2x80x94(C1-C6)-alkyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl and alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH3, OC(O)H, Oxe2x80x94CH2xe2x80x94Ph, NH2, NHxe2x80x94COxe2x80x94CH3 or N(COOCH2Ph)2), SO2xe2x80x94NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, Sxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(CH2)n-phenyl, SOxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(CH2),-phenyl, SO2xe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(CH2)n-phenyl (where n is 0-6 and the phenyl radical may be optionally substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl or NH2), NH2, NHxe2x80x94(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, biphenylyl, Oxe2x80x94(CH2)n-phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), 1,2,3-triazol-5-yl (wherein triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position 1 or 2 by methyl or benzyl);
R2 is NH2, NHR3 or NR4R5, wherein
R3 is (C1-C6)alkyl, CN, CHO, COxe2x80x94NH2, CHxe2x95x90NH, C(S)xe2x80x94NH2, C(xe2x95x90NH)xe2x80x94NH-phenyl (wherein the phenyl ring may be optionally substituted up to two times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), phenyl, CH2-phenyl (wherein the phenyl ring may be optionally substituted up to 3 times by F, Cl, Br, I, OH, NO2, CN, OCF3, Oxe2x80x94(C2-C6)-alkyl, (C2-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), biphenylyl, 1- or 2-naphthyl, 4-pyridyl, 2- or 3-furanyl, 2- or 3- thienyl, 5-tetrazolyl (wherein the biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be optionally substituted up to two times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-66)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), CH2-phenyl, CH2-2-pyridyl or CH2-4-pyridyl (wherein the phenyl or pyridyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2 SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R4 is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3-C6-alkynyl, phenyl or CH2-phenyl (wherein the phenyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R5 is H, C1-C6)-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3-C6-alkynyl, phenyl or CH2-phenyl (wherein the phenyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2) or
R4 and R5 together form one of the groups CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2CH2, CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94CH2xe2x80x94N(CH2-phenyl)xe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2 or CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2;
R6 is (C1-C6)alkyl, acyl, (Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (Cxe2x95x90O)-(C3-C6)-cycloalkyl, phenyl, naphthyl, pyridyl, xe2x80x94SO2-phenyl, or SO2-naphthyl;
and their physiologically tolerated salts and physiologically functional derivatives.
The present invention is directed to a method of treating obesity which encompasses prophylaxis and amelioration of obesity comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of formula I: 
in which
Y is a direct linkage, CH2 or CH2xe2x80x94CH2;
X is CH2, O, NH, NR6 or S;
R1, R1xe2x80x2 are independently H, F, Cl, Br, I, CF3, CN, NO2, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, Oxe2x80x94(C1-C6)-alkyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl and alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH3, OC(O)H, Oxe2x80x94CH2xe2x80x94Ph, NH2, NHxe2x80x94COxe2x80x94CH3 or N(COOCH2Ph)2), SO2xe2x80x94NH2, SO2NH(C1-6)-alkyl SO2N[(C1-C6)-alkyl]2, Sxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(CH2)n-phenyl, SOxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(CH2)n-phenyl, SO2xe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(CH)n-phenyl (where n is 0-6 and the phenyl radical may be optionally substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl or NH2), NH2, NHxe2x80x94(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, biphenylyl, Oxe2x80x94(CH2)n-phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl) 2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), 1,2,3-triazol-5-yl (wherein triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position 1 or 2 by methyl or benzyl);
R2 is NH2, NHR3 or NR4R5, wherein
R3 is (C1-C6)alkyl, CN, CHO, COxe2x80x94NH2, CHxe2x95x90NH, C(S)xe2x80x94NH2, C(xe2x95x90NH)xe2x80x94NH-phenyl (wherein the phenyl ring may be optionally substituted up to two times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), phenyl, CH2-phenyl (wherein the phenyl ring may be optionally substituted up to 3 times by F, Cl, Br, I, OH, NO2, CN, OCF3, Oxe2x80x94(C2-C6)-alkyl, (C2-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), biphenylyl, 1- or 2-naphthyl, 4-pyridyl, 2- or 3-furanyl, 2- or 3- thienyl, 5-tetrazolyl (wherein the biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be optionally substituted up to two times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-66)-alkyl, (C1-C6) NH2, NH(C1-C6)-alkyl, N((C1C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), CH2-phenyl, CH2-pyridyl or CH2-4-pyridyl (wherein the phenyl or pyridyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6-alkyl, N((C1-C1-C6)-alkyl)2SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R4 is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3-C6-alkynyl, phenyl or CH2-phenyl (wherein the phenyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R5 is H, C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3xe2x80x94C6-alkynyl, phenyl or CH2-phenyl (wherein the phenyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2) or
R4 and R5 together form one of the groups CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2CH2, CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94CH2xe2x80x94N(CH2-phenyl)xe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2 or CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2;
R6 is (C1-C6)alkyl, acyl, (Cxe2x95x90O)-(C1-C6)alkyl, (Cxe2x95x90O)xe2x80x94(C3-C6)-cycloalkyl, phenyl, naphthyl, pyridyl, xe2x80x94SO2-phenyl, or SO2-naphthyl;
and their physiologically tolerated salts and physiologically functional derivatives.
A preferred embodiment encompasses treating obesity with a pharmaceutical composition comprising a compound of formula I wherein:
Y is a direct linkage, CH2 or CH2xe2x80x94CH2;
x is CH2 or O;
R1 is F, Cl, Br, I, CF3, CN, NO2, COOH, COO(C1-C6)alkyl, CONH2, CONHC1-C6) alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, Oxe2x80x94(C1-C6)-alkyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl and alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH3, OC(O)H, Oxe2x80x94CH2xe2x80x94Ph, NH2, NHxe2x80x94COxe2x80x94CH3 or N(COOCH2Ph)2), SO2xe2x80x94NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, Sxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(CH2)n-phenyl, SOxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(CH2)n-phenyl, SO2xe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(CH2)n-phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl or NH2), phenyl or O-phenyl (wherein the phenyl radical may be optionally substituted up to two times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R1 is H, F, Cl, Br, I, CF3, CN, NO2, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, Oxe2x80x94(C1-C6)-alkyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl and alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH3, OC(O)H, Oxe2x80x94CH2xe2x80x94Ph, NH2, NHxe2x80x94COxe2x80x94CH3 or N(COOCH2Ph)2), SO2xe2x80x94NH2, SO2NH(C1-C6)xe2x95x90alkyl, SO2N[(C1-C6)-alkyl]2, Sxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(CH2)n-phenyl, SOxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(CH2)n-phenyl, SO2xe2x80x94(C1-C)-alkyl, SO2xe2x80x94(CHO2)n-phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl or NH2), phenyl or O-phenyl (wherein the phenyl radical may be optionally substituted up to two times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R2 NH2, NHR3 or NR4R5, wherein
R3 is (C1-C6)alkyl, CN, CHO, COxe2x80x94NH2, CHxe2x95x90NH, C(S)xe2x80x94NH2, C(xe2x95x90NH)xe2x80x94NHxe2x80x94phenyl (wherein the phenyl ring may be optionally substituted up to two times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2), phenyl or CH2-phenyl (wherein the phenyl ring may be optionally substituted once to 3 times by F, Cl, Br, I, OH, NO2, CN, OCF3, Oxe2x80x94(C2-C6)-alkyl, (C2-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R4 is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3-C6-alkynyl, phenyl or CH2-phenyl (wherein the phenyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2 CN, OCF3, Oxe2x80x94(C1-C6)-alkyl), (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((c1-C6)-alkyl)2 SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2);
R5 is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3-C6-alkynyl, phenyl or CH2-phenyl (wherein the phenyl ring may be optionally substituted once or twice by F, Cl, Br, I, OH, CF3, NO2 CN, OCF3, Oxe2x80x94(C1-C6)-alkyl)2, SO2xe2x80x94CH3, COOH, COOxe2x80x94(C1-C6)-alkyl or CONH2); or
R4 and R5 together form one of the groups CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2, CH2, CH2xe2x80x94CH2xe2x80x94N(CH2-phenyl)xe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2 or CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2;
and their physiologically tolerated salts and physiologically functional derivatives.
A particularly preferred embodiment encompasses treating obesity with a pharmaceutical composition comprising a compound of formula I wherein:
Y is a direct linkage;
x is CH2;
R1 is F, Cl, Br, I, CF3, CN, (C1-C6)-alkyl, Oxe2x80x94(C1-C6)-alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine), SO2xe2x80x94NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, SO2xe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(CH)n-phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl or NH2), phenyl, O-phenyl (wherein the phenyl radical may be optionally substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl or (C1-C6)-alkyl), or pyridyl;
R1xe2x80x2 is H, F, Cl, Br, CF3, CN, (C1-C6)-alkyl, Oxe2x80x94(C1-C6)-alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine), SO2xe2x80x94NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, SO2xe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(CH2)n-phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl or NH2), phenyl (wherein the phenyl radical may be optionally substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl or (C1-C6)-alkyl), or pyridyl;
R2 is NH2, NHR3 or NR4R5, wherein
R3 is (C1-C6)-alkyl, CN, CHO, COxe2x80x94NH2, CHxe2x95x90NH, C(S)xe2x80x94NH2 or C(xe2x95x90NH)xe2x80x94NHxe2x80x94phenyl (wherein the phenyl ring may be optionally substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl or N((C1-C6)-alkyl)2);
R4 is C1-C6-alkyl;
R5 is C1-C6-alkyl; or
R4 and R5 together form a CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 group;
and their physiologically tolerated salts.
The method of treatment contemplated encompasses not only treatment by administration of a pharmaceutical composition which comprises a compound of formula (I) and a pharmaceutically acceptable carrier but also administration of the compound of formula (I) absent a pharmaceutically acceptable carrier.
The invention also relates to the use of compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R1xe2x80x2, R2, R3, R4, R5 and R6 may be either straight-chain or branched.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater solubility in water compared with the initial compounds on which they are based. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula I are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. It is particularly preferred to use the chloride for medical purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
Salts with a pharmaceutically unacceptable anion likewise fall within the scope of the invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in non-therapeutic, for example in vitro, applications.
The term xe2x80x9cphysiologically functional derivativexe2x80x9d used herein refers to any physiologically tolerated derivative of a compound according to the invention, for example an ester, which is able on administration to a mammal, such as, for example, to humans, to form (directly or indirectly) such a compound or an active metabolite thereof.
A further aspect of this invention is the use of prodrugs of compounds of the formula I. Such prodrugs may be metabolized in vivo to a compound of the formula I. These prodrugs may themselves be active or not.
The compounds of the formula I may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the formula I fall within the scope of the invention and are a further aspect of the invention.
All references hereinafter to xe2x80x9ccompound(s) of the formula (I)xe2x80x9d refer to compound(s) of the formula (I) as described above and to the salts, solvates and physiologically functional derivatives thereof as described herein.
The compounds of formula (I) are used in the treatment of obesity. Treatment of obesity encompasses prophylaxis and amelioration of obesity. The treatment regiment involves administering an obesity treating effective amount of a compound of formula (I) as part of a pharmaceutical composition.
The amount of a compound of the formula (I), which is an xe2x80x9ceffective amount,xe2x80x9d that is necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram body weight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which may suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Infusion solutions suitable for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single dose formulations which may be administered orally, such as, for example, tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the above weight data are based on the weight of the aminothiazole ion derived from the salt. The compounds of the formula (I) may be used for prophylaxis or therapy of the abovementioned states themselves as compound, but they are preferably in the form of a pharmaceutical composition with a compatible carrier. The carrier must, of course, be compatible in the sense of compatibility with other ingredients of the composition and not be harmful to the patient""s health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as single dose, for example as tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including further compounds of the formula (I). The pharmaceutical compositions according to the invention may be produced by one of the known pharmaceutical methods which essentially consists of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions according to the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of the formula (I) used in each case. Coated formulations and coated slow-release formulations also fall within the scope of the invention. Acid- and gastric fluid-resistant formulations are preferred. Suitable gastric fluid-resistant coatings comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
The pharmaceutical composition in the inventive method when in the form of a soft gelatin capsule may comprise about 100 mg of a compound of formula (I). The pharmaceutical composition in the inventive method when in the form of an emulsion may comprise about 60 mg of a compound of formula (I). The pharmaceutical composition in the inventive method when in the form of a rectal suppository may comprise about 40 mg of a compound of formula (I). The pharmaceutical composition in the inventive method when in the form of a tablet may comprise about 40 mg of a compound of formula (I). The pharmaceutical composition in the inventive method when in the form of a coated tablet may comprise about 50 mg of a compound of formula (I). The pharmaceutical composition in the inventive method when in the form of a hard gelatin capsule may comprise about 100 mg or about 140 mg of a compound of formula (I). The pharmaceutical composition in the inventive method when in the form of liquid drops may comprise about 100 mg of a compound of formula (I) in 1 ml of drops.
Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, pastilles or tablets, each of which contains a defined amount of the compound of the formula (I); as powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely dispersed solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet may be produced by compressing or shaping the powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets may be produced by tabletting the compound in free-flowing form, such as, for example, a powder or granules, where appropriate mixed with a binder, lubricant, inert diluent and/or one (or more) surface-active/dispersing agents in a suitable machine. Shaped tablets may be produced by shaping, in a suitable machine, the compound which is in powder form and has been moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of the formula (I) with a flavoring, normally sucrose, and gum arabic or tragacanth, and pastilles which contain the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration comprise preferably sterile aqueous preparations of a compound of the formula (I), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations may preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These may be produced by mixing a compound of the formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may be in the form of single plasters which are suitable for long-term close contact with the patient""s epidermis. Plasters of this type suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. As a particular option, the active ingredient may be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
The following preparations serve to illustrate the invention without, however, restricting it.